3- Hexyne, cyclization

Under supercritical C02 at 102 °G, the [2 + 2 + 2]-cyclotrimerization of 3-hexyne with C02 was achieved by use of Ni(cod)2/dppb as a catalyst system (Scheme 27).39,40 In the case of diynes, the intramolecular cyclization/carboxyla-tion took place under high pressure and high temperature (Scheme 28).41,41a... 

Several publications deal with acetylenic halides that can undergo reductive intramolecular cyclization [37]. For example, electrolysis of 6-iodo-l-phenyl-l-hexyne at a carbon cathode gives benzylidenecy-clopentane in 36% yield. 

In a similar manner, the reaction of 5-dimethylsilyl-l-hexyne (111) catalyzed by H2PtCl6 affords 5-exo-dig cyclization product 112 exclusively (equation 47)130. 

Hexyn-l-ol reacts with tosyl iodide to form the ( )-iodovinyl sulfone 185, which can undergo ( -exo-dig cyclization upon treatment with KN(TMS)2 followed by elimination of HI to afford the 3,4-dihydropyran 186 (Scheme 58) C1996T7779, 2005S3613>. 

The kinetics of the cyclization reaction of 5-hexynyllithiums 19 was also studied showing that (6-phenyl-5-hexynyl)lithium (19, R = Ph) has a half-life of ca 6 min at —50.6 °C, whereas cyclization reaction of 5-decynyllithium (19, R = Bu) is some 106 times slower. The rather dramatic increase in the rate of cyclization on going from an alkyl-substituted 5-hexyn-l-yllithium to a phenyl-substituted substrate is most likely a consequence of a reduction in A// due to stabilization of the incipient vinyllithium product by the phenyl group19. It is also interesting to note that the 5-exo-dig cyclization reaction of 19 (R = Bu) is slower than the corresponding 5-exo-trig carbolithiation reaction of 5-hexenyllithium. 

The electroreductive cyclization of some acetylenic halides in DMF has been reported by Moore and Peters. 6-Bromo-l-phenyl-l-hexyne (3) gave three polarographic waves at —2-35 V, —2-60 V and — 2-80 V (vs. S.C.E.). The first wave was correlated with C-Br fission ( -hexyl bromide was reduced at —2-29 V) while the two remaining waves corresponded to triple bond reduction (1-phenyl-1-hexyne gave waves at —2-65 V and —2-88 V). The electrolysis reaction mixture contained both five- and six-membered carbocycles as well as straight-chain reduction products... 

Electrogenerated nickel(I) salen has been used as a catalyst for the reductive intramolecular cyclizations of 6-bromo- and 6-iodo-l-phenyl-1-hexyne [338], the reduction of several Q ,ft)-dihaloalkanes [339], the reductive coupling of 2-bromo- and 2-iodoethanol to prepare 1,4-butanediol [340], the conversion of cyclohexanecarbonyl chloride to a tetramer [341], and the reduction of benzal chloride [342]. 

Cyclization by direct reduction of alkynes linked to halides is usually ineffective. Phenyl-substituted alkynes are more easily reduced than alkyl chlorides but more difficult to reduce than alkyl bromides and iodides. Simple alkynes are more difficult to reduce than any of the halides. Consequently, direct reduction of 6-bromo-l-phenyl-1-hexyne at a potential of cleavage of the C Br bond only affords 12% yield of benzylidenecyclo-pentane, whereas the corresponding chloride gives the saturated benzylcyclopentene in 45% yield [241], or at low substrate concentrations (< 2 mM) the benzylidene cyclopentane (80%) [242]. 

The regiochemical product distribution of the co-cyclization of two or three different alkynes occurs statistically. In some cases carefully controlled reaction conditions allow isolation of a main product from mixed cyclotrimerizations. For example, l,2,3,4-tetraphenyl-5,6-diethylbenzene can be obtained from cobalt-catalyzed reaction of tolane and 3-hexyne in good yield [62]. The first example of an intermolecular, regiospecific cross-benzannulation reaction catalyzed by Pd(PPh3)4 was reported by Yamamoto [63]. The reaction of 2-alky 1-but-l-ene-3-yne with disubstituted diynes leads exclusively in high yields to... 

Yamanaka and associates developed a method for the synthesis of 2-butylindole from the Sonogashira adduct of ethyl 2-bromophenylcarbamate and 1-hexyne [97, 98]. Extension of that method to pyridines led to the synthesis of pyrrolopyridines [99]. However, the method was not applicable to the synthesis of pyrrolo[2,3-6/]pyrimidines. They then developed an alternative route involving an initial S Ar displacement at the 4-position of 4,5-dihalopyrimidine followed by a Sonogashira coupling at the 5-position [100]. Thus, 5-iodopyrimidine 200 was obtained from an S Ar displacement at the 4-position of a 4-chloro-5-iodo-2-methylthiopyrimidine (199). The subsequent Sonogashira reaction of 200 with trimethylacetylene at 80°C resulted in adduct 201, which spontaneously cyclized to pyrrolo[2,3-6/]pyrimidine 202. 

An intramolecular variant of this reaction is the cyclization of 1,6-dilithio- 1-hexyne 144 to dilithiomethylenecyclopentane 145 which we found to take place in 28 % yield on standing in diethyl ether for 10 minutes at —78 °C... 

In both of these examples the organometallic group is locked in close proximity to the triple bond, but Ward4b has shown that such steric coercion is not necessary for the reaction. Thus 6-bromo-1 -phenyl-1 -hexyne (7) is converted into benzylidene-cyclopentane (8) in 60% yield. Ward suggests that the cyclizing species is a radical and not a carbanion ... 

Electroreductive cyclization of acetylenic halides has been extensively studied by Peters, particularly in the case of 6-halo-l-phenyl-l-hexyne. A complicated scheme was proposed for the 6-chloro compound to explain the results. The origin of the cyclized products may be sought among others in the radical formed by direct reduction of the carbon-halogen bond. Another possibility is the reduction of the carbon-carbon triple bond (already recognized previously in the reductive cyclization of bis-propargylamines )... 

Other alkynes undergo fast insertion into the Pd-Me bond, so the intermediate compounds with a bound -alkyne could not be detected (Equation (27)). Additional insertion of alkyne into the new Pd-vinyl bond formed also occurs, followed by further insertions and intramolecular cyclization. The regioselectivity of the first insertion for terminal alkynes depends on the bulkiness of the ancillary ligand, and a correlation between the distribution of products for 1-hexyne and the steric bulk of several substituted diimines was found the more hindered the ligand, the more favored the product of 1,2-insertion. ... 

---